Research

PROGRESS TOWARD TREATMENTS FOR SYNAPTIC DEFECTS IN AUTISM

Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T.

Autism spectrum disorder (ASD) encompasses a range of disorders that are characterized by social and communication deficits and repetitive behaviors. For the majority of affected individuals, the cause of ASD remains unknown, but in at least 20% of the cases, a genetic cause can be identified. There is currently no cure for ASD; however, results from mouse models indicate that some forms of the disorder could be alleviated even at the adult stage. Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis. We propose, given the clinical heterogeneity of ASD, that specific 'synaptic clinical trials' should be designed and launched with the aim of establishing whether phenotype 'reversals' could also occur in humans.

GENOMIC RELATIONSHIPS, NOVEL LOCI, AND PLEIOTROPIC MECHANISMS ACROSS EIGHT PSYCHIATRIC DISORDERS

Cross-Disorder Group of the Psychiatric Genomics Consortium

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

ASSOCIATION BETWEEN SUICIDAL SPECTRUM BEHAVIORS AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Septier M, Stordeur C, Zhang J, Delorme R, Cortese S.

The relationship between ADHD and suicidal spectrum behaviors (SSBs) remains uncertain. We conducted the first meta-analysis on the association between ADHD and SSBs taking possible confounders into account. Based on a pre-registered protocol (PROSPERO-CRD42018093003), we searched Pubmed, Ovid and Web of Knowledge databases through April 6th, 2018, with no language/publication type restrictions, and contacted study authors for unpublished data/information. From a pool of 2798 references, we retained 57 studies. Random-effects models were performed. Study quality was rated using the Newcastle-Ottawa Scale. After pooling crude ORs, we found a significant association between ADHD and suicidal attempts (2.37, 95% CI = 1.64-3.43; I2 = 98.21), suicidal ideations (3.53, 2.94-4.25; I2 = 73.73), suicidal plans (4.54, 2.46-8.37; I2 = 0), and completed suicide (6.69, 3.24-17.39; I2 = 87.53). Results did not substantially change when pooling adjusted ORs. Findings were also in general robust to sensitivity analyses to assess possible moderators. Awareness of the association between ADHD and SSBs should contribute to more effectively prevent SSBs.

METFORMIN FOR WEIGHT GAIN ASSOCIATED WITH SECOND-GENERATION ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Ellul P, Delorme R, Cortese S.

Background: Weight gain is a potentially concerning side effect of second-generation antipsychotics (SGAs). Metformin, a biguanide with antihyperglycemic effects, is used to manage weight gain in adults treated with SGAs.
Objective: The objective of this study was to perform the first systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of metformin on weight gain in children and adolescents treated with SGAs.
Methods: Based on a pre-registered protocol (PROSPERO-CRD42017074839), we searched the PubMed, EMBASE, PsychoINFO, BIOSIS, Science Direct, Cochrane Central, and ClinicalTrials.gov electronic databases through March 2018 (with no restrictions on language, date, or type of publication) for RCTs that assessed the effect of metformin or placebo on body weight in children or adolescents (< 18 years of age) treated with selected SGAs (risperidone, aripiprazole, olanzapine, and clozapine) for any psychiatric disorder. We also contacted relevant drug manufacturers for possible additional pertinent studies/data. A random effects model was used and the quality of the included RCTs was assessed using the Cochrane Risk of Bias tool.
Results: Five RCTs (205 participants in total) were included in the meta-analysis. We found a significant weight decrease in the metformin group compared with placebo after 4, 12, and 16 weeks of treatment {mean difference - 0.98 kg (95% confidence interval [CI] - 1.26, - 0.69); - 1.83 kg (95% CI - 2.47, - 1.18); and - 3.23 kg (95% CI - 5.59, - 0.86), respectively}. A weight decrease at weeks 2 and 8 did not reach statistical significance. The decrease in body mass index (BMI) paralleled that of weight, with a significant effect at weeks 4, 12, and 16. Overall, four studies were rated as unclear, and one study was rated as high, risk of bias.
Conclusion: Meta-analytical evidence shows that metformin might decrease weight in children/adolescents treated with SGAs but additional high-quality evidence is needed. Clinicians need to be aware that this use of metformin is currently off-label.

ANALYSIS OF SHARED HERITABILITY IN COMMON DISORDERS OF THE BRAIN

Brainstorm Consortium, Anttila V, Bulik-Sullivan B, et al.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

A FRAMEWORK TO IDENTIFY CONTRIBUTING GENES IN PATIENTS WITH PHELAN-MCDERMID SYNDROME

Tabet AC, Rolland T, Ducloy M, et al.

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

ATTENTIONAL LAPSES IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: BLANK RATHER THAN WANDERING THOUGHTS

Van den Driessche C, Bastian M, Peyre H, et al.

People with attention-deficit/hyperactivity disorder (ADHD) have difficulties sustaining their attention on external tasks. Such attentional lapses have often been characterized as the simple opposite of external sustained attention, but the different types of attentional lapses, and the subjective experiences to which they correspond, remain unspecified. In this study, we showed that unmedicated children (ages 6-12) with ADHD, when probed during a standard go/no-go task, reported more mind blanking (a mental state characterized by the absence of reportable content) than did control participants. This increase in mind blanking happened at the expense of both focused and wandering thoughts. We also found that methylphenidate reverted the level of mind blanking to baseline (i.e., the level of mind blanking reported by control children without ADHD). However, this restoration led to mind wandering more than to focused attention. In a second experiment, we extended these findings to adults who had subclinical ADHD. These results suggest that executive functions impaired in ADHD are required not only to sustain external attention but also to maintain an internal train of thought.

11Q24.2-25 MICRO-REARRANGEMENTS IN AUTISM SPECTRUM DISORDERS: RELATION TO BRAIN STRUCTURES

Maruani A, Huguet G, Beggiato A, et al.

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy.

GENDER DIFFERENCES IN AUTISM SPECTRUM DISORDERS: DIVERGENCE AMONG SPECIFIC CORE SYMPTOMS

Beggiato A, Peyre H, Maruani A, et al.

Community-based studies have consistently shown a sex ratio heavily skewed towards males in autism spectrum disorders (ASD). The factors underlying this predominance of males are largely unknown, but the way girls score on standardized categorical diagnostic tools might account for the underrecognition of ASD in girls. Despite the existence of different norms for boys and girls with ASD on several major screening tests, the algorithm of the Autism Diagnosis Interview-Revised (ADI-R) has not been reformulated. The aim of our study was to investigate which ADI-R items discriminate between males and females, and to evaluate their weighting in the final diagnosis of autism. We then conducted discriminant analysis (DA) on a sample of 594 probands including 129 females with ASD, recruited by the Paris Autism Research International Sibpair (PARIS) Study. A replication analysis was run on an independent sample of 1716 probands including 338 females with ASD, recruited through the Autism Genetics Resource Exchange (AGRE) program. Entering the raw scores for all ADI-R items as independent variables, the DA correctly classified 78.9% of males and 72.9% of females (P < 0.001) in the PARIS cohort, and 72.2% of males and 68.3% of females (P < 0.0001) in the AGRE cohort. Among the items extracted by the stepwise DA, four belonged to the ADI-R algorithm used for the final diagnosis of ASD. In conclusion, several items of the ADI-R that are taken into account in the diagnosis of autism significantly differentiates between males and females. The potential gender bias thus induced may participate in the underestimation of the prevalence of ASD in females.

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©2020 by Dr. Benjamin Landman. Child Psychiatry, Robert Debre Hospital - Paris